1. Field of Invention
The present invention relates to the field of biological medicines, and more particularly to a use of a plasminogen activator prourokinase (proUK) and variants thereof in facilitated percutaneous coronary intervention (PCI) in patients with accurate myocardial infarction (AMI).
2. Related Art
It is a most important strategy, in early-stage treatment of AMI, to dredge the infarction related artery (IRA) as soon as possible to re-establish an effective forward blood flow, such that an ischemic myocardium is reperfused.
Direct PCI and intravenous thrombolytic therapy are two main methods for dredging the IRA and performing reperfusion to reduce the mortality.
The optimal time for reperfusion to treat AMI is within 1 hr after the onset of the chest pain, and it is critical for reducing the mortality and the disability rate to shorten the time from the onset of the chest pain to the effective reperfusion of the ischemic myocardium. If a direct PCI is performed within 90 min after the medical visit of a patient, the therapeutic effect of the PCI is superior to that of a thrombolytic therapy[1,2,3]. However, due to the limitations such as the PCI equipment in the local medical institution where the patient visits, whether a skilled operator can be in position timely, and inevitable time delay during the transportation of a patient, even in American with very advanced medical services, only 4% of the patients after referral can achieve the treatment objective of receiving direct PCI for reperfusion within 90 min after the medical visit, and about 60-70% of the patients cannot receive direct PCI therapy in time[4].
It is found through studies that, the 30-day mortality of the group of patients that arrive at hospital within 3 hrs after the onset of the chest pain and receive thrombolytic therapy is similar to and even lower than that of the direct PCI group[5,6], and when the delay time of the direct PCI reaches 62 min, compared with the thrombolytic therapy, there is no marked difference in 4-6-week mortality between the two therapy methods[7].
Facilitated PCI refers to an AMI therapeutic schedule in which a thrombolytic drug is administered to an AMI patient for treatment before PCI and then PCI is performed. It is suggested in the AMI treatment guideline of American Heart Association (AHA)/American College of Cardiology (ACC) that, if a direct PCI cannot be implemented within 90 min in the first-visited hospital, the thrombolytic therapy should be immediately implemented on patients without contraindications of thrombolytic therapy; as for patients within 3 hrs after onset, if the conditions for the direct PCI are not satisfied or the delay time of the direct PCI is longer than 1 hr, the thrombolytic therapy is preferred[1]. Due to the feasibility and effectiveness, the thrombolytic therapy is still a reperfusion therapy received by most of the AMI patients, which means that the facilitated PCI has important application meanings in clinical treatment of AMI. However, the effectiveness and safety of the facilitated PCI by using presently approved thrombolytic drugs, such as streptokinase and TPA (including, for example, TNK, reteplase, and alteplase) are significantly poorer than those of the direct PCI[8,9], which may be related to that the TPA thrombolytic drugs may activate the coagulation system upon use and thus the incidence rate of reinfarction is high. Therefore, there is an urgent need to find a new thrombolytic drug applicable in the facilitated PCI.
proUK (which contains 411 amino acids, and has a molecular weight of 46393.65 dalton and an amino acid sequence as shown in SEQ ID NO.1) is a serine proteolysis zymogen having dual characteristics of enzyme and zymogen. After entering the blood circulation intravenously, as a zymogen, proUK or variants thereof will not cause systematic plasminogen activation; and as an enzyme, proUK or variants thereof can dissolve the embolized thrombus with a high selectivity, without acting on hemostatic thrombus at wounds at tissues and organics, and thus prevent hemorrhagic complications upon thrombolytic therapy to the utmost extent. As proUK or variants thereof also have the function of inhibiting platelet aggregation, the incidence rate of reinfarction after thrombolysis may be reduced. It is shown by study results that when treating AMI with rh-PROUK thrombolytic therapy, at 90 min after the administration, the dredging rate of IRA is equivalent to that of TPA, after 24 hr, the reinfarction rate is lower than that of TPA and streptokinase, and after 30 days, the mortality of the patient is lower than that of TPA, streptokinase, and urokinase[10,11]. Presently, there is no report about use of proUK or variants thereof in facilitated PCI in patients with AMI in documents.